Abstract
FYX-051, 4-(5-pyridin-4-yl-1H-[1,2,4]triazol-3-yl)pyridine-2-carbonitrile, is a novel xanthine oxidoreductase inhibitor that can be used for the treatment of gout and hyperuricemia. We examined the metabolism of FYX-051 in rats, dogs, monkeys, and human volunteers after the p.o. administration of this inhibitor. The main metabolites in urine were pyridine N-oxide in rats, triazole N-glucoside in dogs, and triazole N-glucuronide in monkeys and humans, respectively. Furthermore, N-glucuronidation and N-glucosidation were characterized by two types of conjugation: triazole N1- and N2-glucuronidation and N1- and N2-glucosidation, respectively. N1- and N2-glucuronidation was observed in each species, whereas N1- and N2-glucosidation was mainly observed in dogs. With regard to the position of conjugation, N1-conjugation was predominant; this resulted in a considerably higher amount of N1-conjugate in each species than N2-conjugate. The present results indicate that the conjugation reaction observed in FYX-051 metabolism is unique, i.e., N-glucuronidation and N-glucosidation occur at the same position of the triazole ring, resulting in the generation of four different conjugates in mammals. In addition, a urinary profile of FYX-051 metabolites in monkeys and humans was relatively similar; triazole N-glucuronides were mainly excreted in urine.
Footnotes
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.106.011692.
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ABBREVIATIONS: FYX-051, 4-(5-pyridin-4-yl-1H-[1,2,4]triazol-3-yl)pyridine-2-carbonitrile; XOR, xanthine oxidoreductase; MC, methylcellulose; HPLC, high-performance liquid chromatography; LC/MS, liquid chromatography/mass spectrometry; COSY, correlation spectroscopy; NOESY, nuclear Overhauser effect spectroscopy; HSQC, heteronuclear single quantum coherence; HMBC, heteronuclear multiple bond coherence; MS/MS, tandem mass spectrometry; JNJ-10198409, 6,7-(dimethoxy-2,4-dihydroinden-[1,2-C]pyrazol-3-yl)-(3-fluoro-phenyl)-amine.
- Received June 28, 2006.
- Accepted August 14, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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